The multidimensional world of pancreatic cancer:Omic strategies to improve outcome

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer type, which is projected to become the second leading cause of cancer-related deaths in the coming decades. Recently, cancer research has investigated large-scale molecular data from different technologies, so called “big data”. It encompasses different methods referred to as omics. This includes genomics, transcriptomics, proteomics and phosphoproteomics. This thesis the exploits multiple dimensions of omics: from microRNAs to the functionally relevant (phospho)proteome. In Chapter 1, we explored the current knowledge on biology and treatment of PDAC and summarized the three main contributing factors of this devasting disease; (I.) the aggressive growth of PDAC and its complex microenvironment, (II.) the difficulty of adequate diagnosis with current biomarkers, (III.) the need for novel treatments to halt the disease. To decipher the aggressive tumor biology of PDAC, we reviewed current literature of omic studies performed of PDAC in Chapter 2. One of PDAC’s most defining feature is the presence of an abundant desmoplastic microenvironment. This microenvironment, also named stroma, can influence the tumor and its behavior. In Chapter 3, a study of recently identified subtypes of PDAC and stroma is reviewed in depth. In Chapter 4, both compartments were studied by proteomics to identify their individual protein landscapes. In this study, over 5.000 unique proteins were identified. Meta-analysis was performed to validate prognostic markers in gene expression data sets, after which stromal COL11A1 and tumor cell-derived CALB2 were validated by immunohistochemistry in an independent cohort for their association with a poorer prognosis. Expression of proteins is associated with a pathway, often regulated by a common denominator. Thus, analysis of co-expression can identify important biology in a disease. Hence, we studied proteins that are co-expressed in similar patterns across PDAC samples in Chapter 5. In Chapter 6, we reviewed the diagnostic potential of microRNAs in PDAC. These short RNAs have a role in epigenetic regulation. In Chapter 7, we analyzed blood from a cohort of patients suffering from distal cholangiocarcinoma to identify differential microRNAs compared to healthy controls. Chapter 8 described the analysis of RNA from tumor-educated platelets (TEPs) from PDAC patients. Recently, platelets were found to be influenced by tumor cells, so called TEPs. Machine-learning algorithms were implemented to optimize for the most discriminative RNA panel. In Chapter 9, we evaluated secreted proteins of tumor tissue of PDAC and distal cholangiocarcinoma and identified candidate biomarker thrombospondin-2 (THBS2), which was validated in a large second cohort. The final part of this thesis focused on optimalization of treatment of patients with PDAC. Using preclinical models, we explored novel targets and mechanisms of chemoresistance. In Chapter 10, we evaluated differential protein expression of a parental PDAC cell line and its gemcitabine resistant counterpart. In Chapter 11, we explored this gemcitabine-resistant model for its features in vitro and in vivo. To identify novel drug targets, we evaluated kinase expression in the tumor areas of PDAC in Chapter 4. Eph recepter A2 (EPHA2) was found to be abundantly expressed in PDAC cells. Inhibition resulted in enhanced cell death and reduced migration of PDAC cells. Additionally, Chapter 12 explored phosphoproteomics and explored focal adhesion kinase as target in PDAC. In conclusion, the studies described in this thesis exploited the potential of omic strategies to understand the aggressive biology of PDAC, to uncover innovative biomarkers, and identify novel therapeutic options. These findings can contribute to the future diagnosis and treatment of PDAC patients, ultimately improving clinical outcome for these patients

An experimental proposal to study collapse of the wave function in travelling-wave parametric amplifiers

The read-out of a microwave qubit state occurs using an amplification chain that enlarges the quantum state to a signal detectable with a classical measurement apparatus. However, at what point in this process did we really `measure' the quantum state? In order to investigate whether the `measurement' takes place in the amplification chain, we propose to construct a microwave interferometer that has a parametric amplifier added to each of its arms. Feeding the interferometer with single photons, the visibility depends on the gain of the amplifiers and whether a measurement collapse has taken place during the amplification process. We calculate the interference visibility as given by standard quantum mechanics as a function of gain, insertion loss and temperature and find a magnitude of $1/3$ in the limit of large gain without taking into account losses. This number reduces to $0.26$ in case the insertion loss of the amplifiers is $2.2$ dB at a temperature of $50$ mK. We show that if the wave function collapses within the interferometer, we will measure a reduced visibility compared to the prediction from standard quantum mechanics once this collapse process sets in.Comment: 21 pages and 23 figures (including appendices and subfigures). v4: Abstract and introduction rewritten and note on stochasticity of quantum state collapse added to section 6. v5: no content changes w.r.t. v

Key biological processes driving metastatic spread of pancreatic cancer as identified by multi-omics studies.

Pancreatic ductal adenocarcinoma (PDAC) is an extremely aggressive malignancy, characterized by a high metastatic burden, already at the time of diagnosis. The metastatic potential of PDAC is one of the main reasons for the poor outcome next to lack of significant improvement in effective treatments in the last decade. Key mutated driver genes, such as activating KRAS mutations, are concordantly expressed in primary and metastatic tumors. However, the biology behind the metastatic potential of PDAC is not fully understood. Recently, large-scale omic approaches have revealed new mechanisms by which PDAC cells gain their metastatic potency. In particular, genomic studies have shown that multiple heterogeneous subclones reside in the primary tumor with different metastatic potential. The development of metastases may be correlated to a more mesenchymal transcriptomic subtype. However, for cancer cells to survive in a distant organ, metastatic sites need to be modulated into pre-metastatic niches. Proteomic studies identified the influence of exosomes on the Kuppfer cells in the liver, which could function to prepare this tissue for metastatic colonization. Phosphoproteomics adds an extra layer to the established omic techniques by unravelling key functional signaling. Future studies integrating results from these large-scale omic approaches will hopefully improve PDAC prognosis through identification of new therapeutic targets and patient selection tools. In this article, we will review the current knowledge on the biology of PDAC metastasis unravelled by large scale multi-omic approaches

A catalogue of damped Lyman alpha absorption systems and radio flux densities of the background quasars

We present a catalogue of the 322 damped Lyman alpha absorbers taken from the literature. All damped Lyman alpha absorbers are included, with no selection on redshift or quasar magnitude. Of these, 123 are candidates and await confirmation using high resolution spectroscopy. For all 322 objects we catalogue the radio properties of the background quasars, where known. Around 60 quasars have radio flux densities above 0.1 Jy and approximately half of these have optical magnitudes brighter than V = 18. This compilation should prove useful in several areas of extragalactic/cosmological research.Comment: 26 Pages, 12 PS tables, 1 embedded table. Accepted by PASA. Continuously updated online catalogue available at http://www.phys.unsw.edu.au/~sjc/dl

An experimental proposal to study collapse of the wave function in traveling-wave parametric amplifiers

Quantum Matter and Optic

A Sample of Ultra Steep Spectrum Sources Selected from the Westerbork In the Southern Hemisphere (WISH) survey

The 352 MHz Westerbork In the Southern Hemisphere (WISH) survey is the southern extension of the WENSS, covering 1.60 sr between -9 < DEC < -26 to a limiting flux density of ~18 mJy (5sigma). Due to the very low elevation of the observations, the survey has a much lower resolution in declination than in right ascension (54" x 54"cosec(DEC)). A correlation with the 1.4 GHz NVSS shows that the positional accuracy is less constrained in declination than in right ascension, but there is no significant systematic error. We present a source list containing 73570 sources. We correlate this WISH catalogue with the NVSS to construct a sample of faint Ultra Steep Spectrum (USS) sources, which is accessible for follow-up studies with large optical telescopes in the southern hemisphere. This sample is aimed at increasing the number of known high redshift radio galaxies to allow detailed follow-up studies of these massive galaxies and their environments in the early Universe.Comment: 12 Pages, including 5 PostScript figures. Accepted for publication in Astronomy & Astrophysics. The full WISH catalog with 73570 sources is available from http://www.strw.leidenuniv.nl/wenss

Molecular Mechanisms Underlying the Role of MicroRNAs in the Chemoresistance of Pancreatic Cancer

Pancreatic ductal adenocarcinoma (PDAC) is an extremely severe disease where the mortality and incidence rates are almost identical. This is mainly due to late diagnosis and limited response to current treatments. The tumor macroenvironment/microenvironment have been frequently reported as the major contributors to chemoresistance in PDAC, preventing the drugs from reaching their intended site of action (i.e., the malignant duct cells). However, the recent discovery of microRNAs (miRNAs) has provided new directions for research on mechanisms underlying response to chemotherapy. Due to their tissue-/disease-specific expression and high stability in tissues and biofluids, miRNAs represent new promising diagnostic and prognostic/predictive biomarkers and therapeutic targets. Furthermore, several studies have documented that selected miRNAs, such as miR-21 and miR-34a, may influence response to chemotherapy in several tumor types, including PDAC. In this review, we summarize the current knowledge on the role of miRNAs in PDAC and recent advances in understanding their role in chemoresistance through multiple molecular mechanisms

Prognostic and predictive value of human equilibrative nucleoside transporter 1 (hENT1) in extrahepatic cholangiocarcinoma:a translational study

Introduction: Effective (neo) adjuvant chemotherapy for cholangiocarcinoma is lacking due to chemoresistance and the absence of predictive biomarkers. Human equilibrative nucleoside transporter 1 (hENT1) has been described as a potential prognostic and predictive biomarker. In this study, the potential of rabbit-derived (SP120) and murine-derived (10D7G2) antibodies to detect hENT1 expression was compared in tissue samples of patients with extrahepatic cholangiocarcinoma (ECC), and the predictive value of hENT1 was investigated in three ECC cell lines.Methods: Tissues of 71 chemonaïve patients with histological confirmation of ECC were selected and stained with SP120 or 10D7G2 to assess the inter-observer variability for both antibodies and the correlation with overall survival. Concomitantly, gemcitabine sensitivity after hENT1 knockdown was assessed in the ECC cell lines EGI-1, TFK-1, and SK-ChA-1 using sulforhodamine B assays.Results: Scoring immunohistochemistry for hENT1 expression with the use of SP120 antibody resulted in the highest interobserver agreement but did not show a prognostic role of hENT1. However, 10D7G2 showed a prognostic role for hENT1, and a potential predictive role for gemcitabine sensitivity in hENT1 in SK-ChA-1 and TFK-1 cells was found.Discussion: These findings prompt further studies for both preclinical validation of the role of hENT1 and histochemical standardization in cholangiocarcinoma patients treated with gemcitabine-based chemotherapy

Mesoscale modulation of air-sea CO2 flux in Drake Passage

Author Posting. © American Geophysical Union, 2016. This article is posted here by permission of American Geophysical Union for personal use, not for redistribution. The definitive version was published in Journal of Geophysical Research: Oceans 121 (2016): 6635–6649, doi:10.1002/2016JC011714.We investigate the role of mesoscale eddies in modulating air-sea CO2 flux and associated biogeochemical fields in Drake Passage using in situ observations and an eddy-resolving numerical model. Both observations and model show a negative correlation between temperature and partial pressure of CO2 (pCO2) anomalies at the sea surface in austral summer, indicating that warm/cold anticyclonic/cyclonic eddies take up more/less CO2. In austral winter, in contrast, relationships are reversed: warm/cold anticyclonic/cyclonic eddies are characterized by a positive/negative pCO2 anomaly and more/less CO2 outgassing. It is argued that DIC-driven effects on pCO2 are greater than temperature effects in austral summer, leading to a negative correlation. In austral winter, however, the reverse is true. An eddy-centric analysis of the model solution reveals that nitrate and iron respond differently to the same vertical mixing: vertical mixing has a greater impact on iron because its normalized vertical gradient at the base of the surface mixed layer is an order of magnitude greater than that of nitrate.NASA High-End Computing (HEC) Program through the NASA Advanced Supercomputing (NAS) Division at Ames Research Center Grant Number: SMD-15-5752; NSF MOBY project Grant Numbers: (OCE-1048926), OCE-1259388, PLR-1341647, AOAS-0944761, and AOAS-066975; NOAA Climate Program Office Grant Number: (NA12OAR4310058)2017-03-1

Coal-derived rates of atmospheric dust deposition during the Permian

Despite widespread evidence for atmospheric dust deposition prior to the Quaternary, quantitative rate data remains sparse. As dust influences both climate and biological productivity, the absence of quantitative dust data limits the comprehensiveness of models of pre-Quaternary climate and biogeochemical cycles. Here, we propose that inorganic matter contained in coal primarily records atmospheric dust deposition. To test this, we use the average concentration of inorganic matter in Permian coal to map global patterns and deposition rates of atmospheric dust over Pangea. The dust accumulation rate is calculated assuming Permian peat carbon accumulation rates in temperate climates were similar to Holocene rates and accounting for the loss of carbon during coalification. Coal-derived rates vary from 0.02 to 25 g m− 2 year− 1, values that fall within the present-day global range. A well-constrained East–West pattern of dust deposition corresponding to expected palaeoclimate gradients extends across Gondwana with maximum dust deposition rates occurring close to arid regions. A similar pattern is partially defined over the northern hemisphere. Patterns are consistent with the presence of two large global dust plumes centred on the tropics. The spatial patterns of dust deposition were also compared to dust cycle simulations for the Permian made with the Community Climate System Model version 3 (CCSM3). Key differences between the simulations and the coal data are the lack of evidence for an Antarctic dust source, higher than expected dust deposition over N and S China and greater dust deposition rates over Western Gondwana. This new coal-based dust accumulation rate data expands the pre-Neogene quantitative record of atmospheric dust and can help to inform and validate models of global circulation and biogeochemical cycles over the past 350 Myr